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Safer treatment

Orphan drug enters phase III clinical development

Cheryl Guttman Krader

Posted: Friday, December 1, 2017

A phase III clinical trial is now under way investigating the efficacy and safety of the orphan drug polyhexamethylene biguanide (PHMB) 0.08% ophthalmic solution (SIFI) as topical monotherapy for Acanthamoeba keratitis (AK).

Acanthamoeba keratitis presenting with ring abscess. Courtesy of Parwez Hossain MD, PhD

The study is being conducted by the Orphan Drug for Acanthamoeba Keratitis (ODAK) project, a European Commission-funded FP7 project led by the Italian-based pharmaceutical company SIFI. It has a randomised, quadruple-masked design and is comparing PHMB 0.08% plus placebo to current conventional care with PHMB 0.02% plus propamidine.

Recruitment opened at Moorfields Eye Hospital, London, UK, on 8 August, 2017. Other participating centres are located in Southampton and Manchester in the UK, Milan and Venice in Italy, and Katowice, Poland. The study aims to randomise a total of 130 patients to treatment.

John Dart MD, MA, Consultant Ophthalmologist at Moorfields Eye Hospital and Professor at the UCL Institute of Ophthalmology, is coordinating Principal Investigator for the phase III trial.

“The trial is running smoothly. Just six weeks since its launch at our centre, six eligible patients have already agreed to enter,” he told EuroTimes.

Patients with suspected AK will need to travel to one of the participating centres to enter the trial, explained Parwez Hossain MD, PhD, Consultant Ophthalmologist, Southampton General Hospital, who is the investigator at the Southampton centre.

“Our early experience suggests, however, that more than 70% of patients with suspected AK will be found eligible for enrolment,” he commented.

ADDRESSING A THERAPEUTIC NEED
The development of PHMB 0.08% as topical monotherapy for AK aims to provide better, safer treatment for this severe, sight-threatening infection. AK is a significant cause of unilateral visual loss in contact lens wearers. Earlier diagnosis portends a better outcome, but even with early diagnosis, AK management involves many months of treatment, often more than one year, with no guarantee of resolution. Additionally, current treatment regimens are quite toxic to the ocular surface,” said Dr Hossain.

“Currently, PHMB 0.02% is the most effective treatment for AK, but findings from preclinical studies and a human phase I volunteer study indicate that PHMB 0.08% monotherapy has low toxicity and is well tolerated. The ODAK study will establish whether PHMB monotherapy with this new formulation and higher concentration will can shorten the treatment time whilst causing less ocular surface toxicity than combination therapy with two drugs,” he explained.

PRACTICAL PROTOCOL
The phase III study is also evaluating concomitant anti-inflammatory treatment and management of patients with comorbid bacterial infection.

“Inflammatory complications of AK mandate the use of corticosteroid drops and oral non-steroidal anti-inflammatory drugs (NSAIDs) in up to 75% of patients. The risk-benefit of anti-inflammatory treatment has been controversial, but we reported in a retrospective study that it was not associated with worse outcomes when initiated after starting anti-amoebic therapy,” said Dr Dart.

All ODAK investigators will use the same topical corticosteroid with the same oral NSAID for anti-inflammatory therapy, but the dosing can be adjusted according to patient response. Anti-inflammatory treatment can only be introduced after three weeks of anti-amoebic therapy in patients not using any anti-inflammatory medications at study entry, and there are additional criteria about managing patients on existing anti-inflammatory treatment.

“Standardising the anti-inflammatory therapy will reduce the variables we have to control for when analysing the outcomes and results in a coherent and simpler treatment protocol,” Dr Dart said.

The inclusion of patients with bacterial co-infection in the trial recognises its presence in up to 20% of patients with AK. Antibiotic treatment for patients with active bacterial co-infection is also standardised.

“We wanted this to be a real-world trial. Excluding individuals with bacterial co-infection would have left out a substantial group of AK patients for whom our results would be meaningless. Our overall treatment protocol is complex, but if it is effective, this study will give substantial guidance to clinicians worldwide regarding how to manage AK and provide a gold standard against which the results of  modifications to treatment can be measured,” Dr Dart said.

For more information about the trial please contact: odak-office@odak-project.eu.

John Dart: j.dart@ucl.ac.uk
Parwez Hossain: P.N.Hossain@soton.ac.uk